Drug Design, Docking Studies, Synthesis And Biological Evaluation Of Certain Optimized Lead Derivatives Of Triazoles As Inhibitors Of Cytochrome P450 14 -α- Demethylase

Abstract

Cytochrome P450 14α-Demethylase (CYP51A1) is the target enzyme for antifungal drugs, which inhibit ergosterol biosynthesis in fungal cell walls, resulting in antifungal action. The increasing prevalence of life-threatening systemic fungal infections underscores the need for new, more potent, and broader-spectrum antifungal drugs. In this context, certain triazole derivatives were designed, synthesized, and evaluated for antifungal activity. The inhibitory action of these drugs on CYP51A1 was predicted through molecular docking studies using HEX, GLIDE, and GOLD software. The enzyme's structure and active site were identified from the Protein Data Bank (PDB) and literature. Triazoles, selected as the lead moiety, were optimized via molecular docking. Based on the best docking scores, selected triazole derivatives were synthesized and tested against Candida albicans and Aspergillus niger. Experimental results showed all synthesized compounds were active against Candida albicans but inactive against Aspergillus niger. The halogenated triazole derivative with the highest docking score exhibited the largest zone of inhibition compared to other synthesized compounds, aligning computational and experimental results. These findings, combining experimental data and computational evidence, can guide further protein-ligand design and provide insights into active-site interactions.